DNA synthesis inhibition via purine analog incorporation

Purine analogs, such as 6-mercaptopurine, 6-thioguanine, and fludarabine, are structurally similar to natural purine bases. After conversion to their active nucleoside triphosphate forms, they are incorporated into DNA by DNA polymerases in place of adenine or guanine. Their abnormal structure either blocks further DNA elongation (chain termination) or triggers DNA repair pathways, ultimately resulting in cell death or apoptosis. These agents are widely used in the treatment of hematological malignancies and as immunosuppressants, but their clinical use is limited by risks of bone marrow suppression, mutagenesis, and the development of resistance. The therapeutic selectivity is sometimes enhanced by co-administering metabolizing enzyme inhibitors, and TPMT genotyping is employed to predict risk of adverse effects in patients receiving thiopurines.

Other names

Purine analog-mediated DNA chain terminationPurine analog incorporation into DNADNA polymerase inhibition by purine analogsNucleoside analog-induced DNA synthesis inhibition

Purine analogs are phosphorylated to triphosphate forms and incorporated into DNA by polymerases. Chain termination—once incorporated, further DNA elongation is blocked. DNA polymerase inhibition—some analogs directly inhibit DNA polymerases. Induction of lethal DNA damage via mismatch repair activation. Disruption of nucleotide pools and biosynthesis.